The effect of disc1 on the stress response in zebrafish

Stressful experiences in animals trigger responses that lead to adaptive changes. These changes to physiology, metabolism and behaviour are mediated by the stress axis, which acts to maintain or restore homeostasis. Stress in early life is linked to the development of adult-onset psychiatric disorders in humans. Evidence from animal models has demonstrated that stress can affect behaviour, endocrine function and gene expression. Studies in mice also suggest that the combination of stress and a genetic predisposition can result in abnormal behaviours that resemble psychiatric disease. One such genetic factor is Disrupted-In-Schizophrenia-1 (DISC1). A translocation in DISC1 segregates with a high prevalence of mental illness in a large human family. The DISC1 protein is implicated in a wide variety of roles in the nervous system. Mouse models of DISC1 exhibit various behavioural abnormalities that have been likened to anxiety in humans. Recently, it has been demonstrated that mutant DISC1 mice display abnormal phenotypes in response to stress, thereby opening an avenue to investigate the role of DISC1 in the stress response. The zebrafish is powerful study system to address such a topic. Zebrafish are genetically tractable, exhibit quantifiable behaviours and have relatively simple brains that offer a good level of functional homology with humans [1]. The work described in this thesis utilises novel zebrafish models of disc1, the orthologue of the genetic risk factor in humans, which have not been previously examined with respect to stress responses. I describe studies in which I have analysed disc1 mutant zebrafish in terms of behavioural and endocrine responses to stress and investigated the expression of genes linked to hypothalamic development and the stress response. When exposed to an acute chemical stressor, wild type zebrafish modulated their behaviour and upregulate cortisol synthesis. Conversely, disc1 mutants typically do not modulate their behaviour or cortisol synthesis when exposed to the stressor. Mutants also displayed abnormal expression of a number of genes in the hypothalamus, which are critical to normal hypothalamic development. These findings suggest that disc1 alters stress axis function via abnormal hypothalamic development.